tbuckley/cabot-search huggingface dataset:
P934: DARATUMUMAB + LENALIDOMIDE, BORTEZOMIB, AND DEXAMETHASONE IN TRANSPLANT-ELIGIBLE NEWLY DIAGNOSED MULTIPLE MYELOMA: A POST HOC ANALYSIS OF SUSTAINED MINIMAL RESIDUAL DISEASE NEGATIVITY FROM GRIFFIN
Authors: C. Rodriguez, J. L. Kaufman, J. Laubach, D. W. Sborov, B. Reeves, A. Chari, R. Silbermann, L. J. Costa, L. D. Anderson, N. Nathwani, N. Shah, N. Bumma, A. Jakubowiak, R. Z. Orlowski, H. Pei, A. Cortoos, S. Patel, T. S. Lin, P. G. Richardson, P. M. Voorhees
Journal: HemaSphere (2022)

Background: In the primary analysis of the phase 2 randomized GRIFFIN study, Daratumumab (DARA) + lenalidomide, bortezomib, and dexamethasone (D-RVd) improved the stringent complete response (sCR) rate by end of consolidation for transplant-eligible newly diagnosed multiple myeloma (NDMM) (42.4% vs 32.0%; 1-sided P = 0.068). With longer follow-up (median, 38.6 mo), D-RVd vs RVd improved minimal residual disease (MRD)-negativity (10–5) rates in clinically relevant subgroups (ISS stage III, 71% vs 36%; high cytogenetic risk, 44% vs 29% [del17p, t(4;14), or t(14;16)]; revised high cytogenetic risk, 55% vs 32% [del17p, t(4;14), t(14;16), t(14;20), or gain 1q]). Aims: In this post-hoc analysis we present results of sustained MRD negativity (median follow-up, 38.6 mo) in the same subgroups and in patients (pts) with ≥CR. Methods: Transplant-eligible NDMM pts were randomized 1:1 to 4 D-RVd/RVd induction cycles, ASCT, 2 D-RVd/RVd consolidation cycles, and 2 years of maintenance therapy with lenalidomide (R) ± DARA. For induction/consolidation (21-day cycles), pts received R (25 mg PO Days [D] 1-14), V (1.3 mg/m2 SC D1, 4, 8, 11), and d (40 mg PO weekly) ± DARA (16 mg/kg IV D1, 8, 15 of Cycles 1-4 and D1 of Cycles 5-6). In maintenance (28-day cycles), pts received R (10 mg PO D1-21; if tolerated, 15 mg in Cycles 10+) ± DARA (16 mg/kg IV Q8W/Q4W or 1800 mg SC per protocol amendments). The primary endpoint was sCR rate by end of consolidation. Results: The following features were balanced among randomized pts (D-RVd, n = 104; RVd, n = 103): high cytogenetic risk (16; 14), revised high cytogenetic risk (42; 37), gain 1q (34; 28), and ISS stage III (14; 14). Sustained MRD-negativity rates at 10–5 lasting ≥6 and ≥12 months were higher for D-RVd vs RVd among all high-risk subgroups (Table). D-RVd was superior to RVd for rates of sustained MRD negativity lasting ≥12 months for pts with ≥CR (53.7% vs 20.3%) and sCR (59.1% vs 17.4%; Table). Among all pts with sustained MRD negativity, only 1 D-RVd pt subsequently had disease progression, and 1 RVd pt died. Additional data on MRD at 10–6 and PFS will be presented. Image:Summary/Conclusion: MRD data in GRIFFIN show that the addition of DARA to RVd induction/consolidation and R maintenance may lead to durable MRD-negativity (10–5) rates in pts with transplant-eligible NDMM with high cytogenetic risk, ISS stage III, and those who achieve ≥CR or sCR, however larger studies are needed.
PB2028: TREATING MULTIPLE MYELOMA IN A RESOURCE-LIMITED SETTING: REAL-WORLD OUTCOMES
Authors: G. Martinez, F. Seguro, M. Jacomassi, H. Visnadi, M. Atanazio, R. Szor, P. Neffá, T. Pereira, W. Silva, P. Dorlhiac-Llacer, R. Velasques, L. Bassolli, V. Rocha
Journal: HemaSphere (2022)

Background: Over 70% of the Brazilian population (> 150 million people) do not have access to private health care. Alkylating agents, thalidomide, and autologous stem cell transplantation (ASCT) are the mainstay of newly diagnosed multiple myeloma (NDMM) treatment in the public health care system. Therefore, real-life data from resource-limited countries are scarce and essential to optimize the incorporation of new technologies into this scenario. Aims: Describe characteristics of patients with NDMM, access to therapy, and outcomes, including overall survival (OS) and progression-free survival (PFS). Methods: Retrospective chart study including all patients with NDMM treated at Hospital das Clinicas de São Paulo Complex between 2009 and 2019. Results: A total of 816 patients with NDMM were included. Mean age was 63 years and 55% were male. At the diagnosis, 91% of patients had bone lesions, 56% anemia, 41% hypercalcemia, and 26% presented with impaired renal function. Regarding the clinical stage, 88% were Durie Salmon III clinical stage, and 46% were ISS III stage. Median follow-up time was 5 years. A triplet regimen (cyclophosphamide, dexamethasone, and thalidomide) was the most prescribed in the frontline (446/792, 56%), followed by alkylating agent + dexamethasone regimens (281/792, 27%). Only three patients (0.4%) in this cohort received bortezomib upfront. 379 (46%) were referred to ASCT for consolidation, and 257 (25%) proceeded with it in the first-line treatment. 36% of the patients received three or more lines of therapy. Patients who underwent ASCT had fewer comorbidities by Charlson’s index, lower ECOG at diagnosis, and fewer ISS stage III patients (31%) (p<0.001 for all), as shown in Table 1. Only 16% of the patients over 60 years underwent ASCT. Median time from diagnosis to transplant was ten months. Early mortality (≤ 120 days after diagnosis) was 9.7%, mainly due to infection. For the whole cohort, the overall response rate (ORR) after the first induction was 408/647 (63%), and 144 (22%) had disease progression. PFS and OS were 1.7 years (95% CI 1.6-1.9) and 3.7 years (95% CI 3.4-4.2), respectively. Median OS for patients that received ASCT was 5.9 (95%CI 5.1-7.8) years. Image:Summary/Conclusion: This real-world cohort demonstrated that the available therapy in a resource-limited setting is far from the current gold standard for NDMM. Alkylating-based therapy results in suboptimal response rates, while the ASCT procedure is not timely available for all patients. In addition, poor clinical status and advanced disease may impact the choice of not using triplet regimens upfront. Early diagnosis, incorporating proteasome inhibitors and newer agents into the frontline, and ASCT availability are the major initiatives to decrease the disparity between rich and developing countries.
PB1974: MULTIVARIATE SPECTRAL BIOTYPING OF EXTRAMEDULLARY MULTIPLE MYELOMA
Authors: M. Vlachová, J. Gregorová, S. Adamová, L. Pečinka, L. Moráň, V. Porokh, M. Štork, L. Pour, J. Havel, P. Vaňhara, S. Ševčíková
Journal: HemaSphere (2022)

Background: Multiple myeloma (MM) is the second most common hematological malignancy of the elderly. The bone marrow is infiltrated by malignant plasma cells. MM may progress into so-called extramedullary disease (EMD) - EMD occurs when a subclone of malignant plasma cells migrates out of the bone marrow and infiltrates soft tissues. Despite recent progress, pathogenesis of EMD still needs to be clarified. Aims: We focused on the analysis of low molecular weight molecules in peripheral blood of 20 MM and 20 EMD patients using MALDI-TOF mass spectrometry to create a tool for identification of MM and EMD, and discrimination of individual types. Methods: Matrix-Assisted Laser Desorption/Ionization Time-of Flight Mass Spectrometry (MALDI-TOF MS) has become an indispensable research tool, which is used for analysis of biomolecules and various organic molecules. Artificial Neural Networks (ANN) are components of artificial intelligence inspired by biological neural networks. Using ANN, we can model complex non-linear systems, as previously published. In our previous study, we recorded mass spectra of MM and healthy donor samples. ANN specifically predicted MM samples with high sensitivity, specificity and accuracy. The same approach as applied on MM and EMD. Results: The RStudio was used for statistical analysis, where the data were evaluated using Principal Component Analysis (PCA) and Partial least squares discriminant analysis (PSL-DA). Using MALDI-TOF MS, it was possible to distinguish between samples of MM patients and healthy donors, as well as MM and EMD patients. Informative patterns in mass spectra served as inputs for ANN that specifically distinguished between healthy donors and patients. Summary/Conclusion: We demonstrated that using MALDI-TOF MS coupled with ANN is a useful tool that can distinguish between healthy donors and MM/EMD patients. Thus, it can be used as a fast alternative to conventional analyses. This study was supported by grant of the Ministry of Health of the Czech Republic, NU21-03-00076.
FOXP3 exon 2 controls T <sub>reg</sub> stability and autoimmunity
Authors: Jianguang Du, Qun Wang, Shuangshuang Yang, Si Chen, Yongyao Fu, Sabine Spath, Phillip Domeier, David Hagin, Stephanie Anover-Sombke, Maya Haouili, Sheng Liu, Jun Wan, Lei Han, Juli Liu, Lei Yang, Neel Sangani, Yujing Li, Xiongbin Lu, Sarath Chandra Janga, Mark H. Kaplan, Troy R. Torgerson, Steven F. Ziegler, Baohua Zhou
Journal: Science Immunology (2022)

Differing from the mouse Foxp3 gene that encodes only one protein product, human FOXP3 encodes two major isoforms through alternative splicing—a longer isoform (FOXP3 FL) containing all the coding exons and a shorter isoform lacking the amino acids encoded by exon 2 (FOXP3 ΔE2). The two isoforms are naturally expressed in humans, yet their differences in controlling regulatory T cell phenotype and functionality remain unclear. In this study, we show that patients expressing only the shorter isoform fail to maintain self-tolerance and develop immunodeficiency, polyendocrinopathy, and enteropathy X-linked (IPEX) syndrome. Mice with Foxp3 exon 2 deletion have excessive follicular helper T (T FH ) and germinal center B (GC B) cell responses, and develop systemic autoimmune disease with anti-dsDNA and antinuclear autoantibody production, as well as immune complex glomerulonephritis. Despite having normal suppressive function in in vitro assays, regulatory T cells expressing FOXP3 ΔE2 are unstable and sufficient to induce autoimmunity when transferred into Tcrb -deficient mice. Mechanistically, the FOXP3 ΔE2 isoform allows increased expression of selected cytokines, but decreased expression of a set of positive regulators of Foxp3 without altered binding to these gene loci. These findings uncover indispensable functions of the FOXP3 exon 2 region, highlighting a role in regulating a transcriptional program that maintains T reg stability and immune homeostasis.
Abstract SY24-04: And by a sleep to say we end: Tumor dormancy, aging, and recurrent disease
Authors: Ashani T. Weeraratna
Journal: Cancer Research (2022)

Abstract Disseminated cancer cells (DCCs) that escape the primary site can seed in distal tissues, but may take several years, or even decades to grow out into overt metastases, a phenomenon termed tumor dormancy. Despite its importance in metastasis and residual disease, few studies have been able to successfully model or characterize dormancy within melanoma. Here, we show that age-related changes in the lung microenvironment facilitate a permissive niche for efficient outgrowth of disseminated dormant tumor cells, in contrast to the aged skin, where age-related changes suppress melanoma growth but drive dissemination. A model of melanoma progression that addresses these microenvironmental complexities is the phenotype switching model, which argues that melanoma cells switch between a proliferative cell state and a slower-cycling, invasive state. We have previously shown that dermal fibroblasts are key orchestrators of promoting phenotype switching in primary melanoma tumors via changes in the secretion of soluble factors during aging. Our new data identify Wnt5A as a master regulator of activating melanoma DCC dormancy within the lung, which initially enables efficient dissemination and seeding of melanoma cells in metastatic niches. Age-induced reprogramming of lung fibroblasts increases their secretion of soluble Wnt factors enabling efficient metastatic outgrowth. Overall, we find that age-induced changes in distal metastatic microenvironments promotes efficient reactivation of dormant melanoma cells in the lung. Further these changes are also reflected in the response of tumor cells to therapy, linking dormancy to recurrent disease. Citation Format: Ashani T. Weeraratna. And by a sleep to say we end: Tumor dormancy, aging, and recurrent disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY24-04.
PB1868: EXPERIENCE IN THE TREATMENT OF HAIRY CELL LEUKEMIA IN KAZAKHSTAN.
Authors: N. Kemelbekov, S. Gabbasova, Z. Dushimova, R. Ramazanova, Z. Amankulov, B. Nassipov, G. Sagyndikov, A. Jazyltayeva, A. Koshkarbayeva, M. Donenbaeva
Journal: HemaSphere (2022)

Background: Hairy cell leukemia is a rare oncohematological disease that manifests itself in damage to the bone marrow and spleen. One of the characteristic changes in the bone marrow are large cells, a rounded nucleus and thin outgrowths - “hairs” of the cytoplasm. The standard of care are drugs: cladribine and purine analogues-pentostatin. The complexity of therapy lies in the high risk of infections due to prolonged cytopenia during therapy. Aims: The aim of the study was to analyze the detection of hairy cell leukemia in Kazakhstan and the effectiveness of the cladribine regimen. Methods: In Kazakhstan 30 patients were diagnosed over the last 5-year period. All patients underwent cytological, histological examination of the bone marrow, bone marrow immunophenotyping. Thirty patient s were treated with cladribine intravenous infusion 0.1 mg/kg per day for 7 days. The average age was 54.6years (from 29 to 80 years), men-10, women-20. With a median follow-up of 4 years, the complete response (CR) was -25 patients, progression of disease – 3 patients, two patients die from infection. Results: Median duration of response was 38 months (range, 0.0+ to 52.0+). Median overall survival was not reached in all patients with CR. All patients had hematological complications in the form of grade 4 leukopenia - 30 patients, grade 4 thrombocytopenia - 28 patients, grade 3 thrombocytopenia – 2, patients grade 2 anemia - 9 patients. Emetic syndrome in the form of vomiting of the 3rd degree was in one patient, diarrhea of the 2nd degree in one patient. Eleven patients had febrile neutropenia. Two patients had a fatal outcome due to the development of pneumonia and subsequent sepsis. Summary/Conclusion: Treatment of patients with hairy cell leukemia with a purine analogue showed high efficiency, but was accompanied by prolonged cytopenia and frequent secondary infection. It is necessary to consider the issue of vaccination of this category of patients with anti-pneumococcal vaccine and also to conduct continuous monitoring. Ten patients with CR were vaccinated against coronavirus infection.
PB2266: INFECTIVE ENDOCARDITIS IN NEUTROPENIC PATIENTS: A SYSTEMATIC REVIEW
Authors: M. Guaraná, E. Beteille, M. Nucci
Journal: HemaSphere (2022)

Background: Infective endocarditis (IE) is a serious infection in non-neutropenic patients. We have published a low incidence of IE caused by viridans streptococci in neutropenic patients. Aims: To evaluate the frequency of IE caused by pathogens other than viridans streptococci in neutropenic patients and characterize the clinical presentation of IE in such patients. Methods: We performed a computerized search of MEDLINE (PubMed version) from May 1948 through October 2021 using the keywords combinations “(neutropenia or neutropenic) endocarditis” and “endocarditis leukemia”. Additional hand searching in reference lists was performed in all articles that met eligibility criteria. All studies in English language that included patients with documented neutropenia during the episode of IE were selected Results: Among 570 studies, 21 were selected, reporting only 22 episodes of IE caused by bacteria and fungi (11 cases each). Cases of IE caused by bacteria involved mostly left heart valves while cases caused by fungi involved the right heart. A new cardiac murmur was the most frequent clinical presentation and the majority of patients with IE had no pre-existing valve abnormalities. Summary/Conclusion: Given the rarity of IE in neutropenic patients, routine investigation with echocardiography seems not indicated.
Abstract SY43-02: Adapting clinical radiation therapy to immune checkpoint blockade
Authors: Silvia C. Formenti
Journal: Cancer Research (2022)

Abstract Focal radiation therapy has demonstrated to elicit inflammatory and immune responses that contribute to cancer immunosurveillance, but may also have unwanted systemic effects. The application of ionizing radiation to cancer, which is the basis for the field of radiation oncology, has evolved to define and exploit the therapeutic window between radiation cytocidal effects in tumors versus those in normal tissue. The original standardization of specific dose-fractionation regimens reflected the results of decades of empirical experience to find the best balance between local control of the irradiated cancer and the mitigation of risk for acute and late sequelae in the exposed normal tissues. More than a century of research in radiation biology has elucidated how radiation damage recruits a classical inflammation response, activates pathways to repair tissues through scavenging of cellular debris and canonical wound repair mechanisms that aim at recovering tissue integrity. Intrinsic to this process is a robust dampening of immunogenic signals, common to those associated with wound repair, to prevent triggering of auto-immune rejections of inflamed tissues. At the same time, radiation has proimmunogenic effects, that recruit both the innate arm of the immune system (acute induction of IFN pathways) and the adaptive arm, through radiation-induced neoepitopes and enhanced cross presentation. Strategies to uncouple these opposite effects are the focus of research efforts in multiple radiation biology laboratories, worldwide. The emergence of modern cancer immunotherapy offers the opportunity to further dissect such strategies. Recent evidence suggest a new role for focal radiotherapy, to partnering and synergize with immune checkpoint blockade (ICB). Evidence is emerging both preclinically and in the clinical setting that optimal integration of radiotherapy with the available immune modifiers might require changes in standard radiation oncology practices. Variables like the type of treatment fields, the inclusion of draining nodal stations, the degree of exposure of circulating immune cells, the type of dose-fractionation and the timing of radiotherapy during ICB all can affect the success of immunoradiotherapy combinations. Hence, defining the parameters for adapting classic radiation therapy to best integrate with ICB remains a fundamental area of investigation, as it is integral to a successful partnership with immunotherapy. Citation Format: Silvia C. Formenti. Adapting clinical radiation therapy to immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY43-02.
P1512: HEART FAILURE IN THALASSEMIA MAJOR: TIME FOR NEW CARDIOVASCULAR MAGNETIC RESONCE MARKERS?
Authors: A. Meloni, L. Pistoia, N. Martini, D. Visceglie, P. M. G. Sanna, M. Murgia, A. Barone, P. Giovangrossi, G. Alberini, V. Positano, F. Cademartiri
Journal: HemaSphere (2022)

Background: Altough T2* cardiovascular magnetic resonance (CMR) represents the non-invasive gold standard for myocardial iron overload (MIO) assessment, native myocardial T1 mapping was demonstrated more sensitive in presence of small amounts of iron. The myocardial extracellular volume (ECV) by CMR has been introduced as a surrogate marker of diffuse interstitial myocardial fibrosis, significantly associated with MIO. Aims: We explored the clinical impact of ECV mapping for detecting heart failure in thalassemia major (TM). Methods: 108 β-TM patients (62 females, 40.16±8.83 years), consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network, underwent CMR. T2* and native and post-contrast T1 values were assessed in all 16 myocardial segments. Segmental ECV values were calculated with input of native and post-contrast myocardial segmental and blood pool T1 values and same-day hematocrit. Global value was the mean of all segmental values. Results: Patients without and with at least one cardiovascular risk factor showed comparable global ECV values (31.89±5.65% vs 33.00±7.46%; P=0.404). N-terminal pro-BNP levels, a proven diagnostic biomarker for the diagnosis and prognosis of patients with heart failure, were significantly correlated with global ECV values (R=0.237; P=0.016) but not with global heart T2* or T1 values. Significant MIO (global heart T2*<20 ms) was found in 9 (8.3%) patients. Global ECV values were significantly higher in patients with significant MIO than in patients without significant MIO (40.07±10.62% vs 31.85±5.71%; P=0.049). Ten (9.3%) patients had a history of heart failure. Compared to patients without heart failure, patients with a history of heart failure showed significantly lower global heart T1 values (882.68±125.46 ms vs 962.66±81.90 ms; P=0.047) and significantly higher global heart ECV values (36.63±9.41 vs 32.12±6.14 ms; P=0.039) (Figure). Global heart T2* values tended to be lower in patients with heart failure than in patients free of heart failure, but the difference was not significant (30.44±14.53 vs 38.24±8.63 ms; P=0.077). Image:Summary/Conclusion: In our population of well treated patients, generally not heavily loaded at the cardiac level, native T1 and ECV values turned out to be a associated with heart failure, more strongly than global heart T2* values. So, when possible, the ECV assessment should be included in the routine CMR of TM patients. Longitudinal prospective studies are needed to clarify the temporal association between MIO and diffuse fibrosis. Moreover, the potential of treatments targeted at interstitial fibrosis to reduce the risk of heart failure should be investigated, especially in TM patients refractory to iron chelating therapy.